Parvalbumin Interneuron Impairment Leads to Synaptic Transmission Deficits and Seizures in SCN8A Epileptic Encephalopathy

Abstract

SCN8A epileptic encephalopathy (EE) is a severe epilepsy syndrome resulting from de novo mutations in the voltage-gated sodium channel Nav1.6, encoded by the gene SCN8A. Nav1.6 is expressed in both excitatory and inhibitory neurons, yet previous studies have primarily focused on the impact SCN8A mutations have on excitatory neuron function, with limited studies on the importance of inhibitory interneurons to seizure onset and progression. Inhibitory interneurons are critical in balancing network excitability and are known to contribute to the pathophysiology of other epilepsies. Parvalbumin (PV) interneurons are the most prominent inhibitory neuron subtype in the brain, making up about 40% of inhibitory interneurons. Notably, PV interneurons express high levels of Nav1.6. To assess the role of PV interneurons within SCN8A EE, we used two mouse models harboring patient-derived SCN8A gain-of-function mutations, Scn8aD/+, where the SCN8A mutation N1768D is expressed globally, and Scn8aW/+-PV, where the SCN8A mutation R1872W is selectively expressed in PV interneurons. Expression of the R1872W SCN8A mutation selectively in PV interneurons led to the development of spontaneous seizures in Scn8aW/+-PV mice and seizure-induced death, decreasing survival compared to wild-type. Electrophysiology studies showed that PV interneurons in Scn8aD/+ and Scn8aW/+-PV mice were susceptible to depolarization block, a state of action potential failure. Scn8aD/+ and Scn8aW/+-PV interneurons also exhibited increased persistent sodium current, a hallmark of SCN8A gain-of-function mutations that contributes to depolarization block. Evaluation of synaptic connections between PV interneurons and pyramidal cells showed an increase in synaptic transmission failure at high frequencies (80-120Hz) as well as an increase in synaptic latency in Scn8aD/+ and Scn8aW/+-PV interneurons. These data indicate a distinct impairment of synaptic transmission in SCN8A EE, potentially decreasing overall cortical network inhibition. Together, our novel findings indicate that failure of PV interneuron spiking via depolarization block along with frequency-dependent inhibitory synaptic impairment likely elicits an overall reduction in the inhibitory drive in SCN8A EE, leading to unchecked excitation and ultimately resulting in seizures and seizure-induced death.